Harrisons Manual Of Oncology

HARRISON
’
S
Manual of
Oncology
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Medical
HARRISON
’
S
Manual of

Oncology
Bruce A. Chabner, M.D.
Clinical Director
Massachusetts General Hospital Cancer Center
Associate Director of Clinical Sciences
Dana-Farber/Harvard Cancer Center
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Thomas J. Lynch, Jr., M.D.
Chief, Hematology-Oncology
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Dan L. Longo, A.B., M.D., F.A.C.P.
Scientific Director
National Institute on Aging
National Institutes of Health
Bethesda and Baltimore, Maryland
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DOI: 10.1036/0071411895
Contributors ix
Preface xix
Acknowledgments xx
Introduction to Cancer Pharmacology (Bruce A. Chabner) xxi
1 Antimetabolites: Fluoropyrimidines and Other Agents
(Bruce A. Chabner)1
2 Antifolates (Bruce A. Chabner)18
3 The Taxanes and Their Derivatives
(Hamza Mujagic and Bruce Chabner)24
4 Vinca Alkaloids (Bruce A. Chabner)32
5 Topoisomerase Inhibitors: Camptothecins, Anthracyclines, and
Etoposide (Dan Zuckerman and Bruce A. Chabner)35
6 Adduct-Forming Agents: Alkylating Agents and Platinum Analogs
(Bruce A. Chabner)49
7 Thalidomide and Its Analogs (Hamza Mujagic)56
8 Bleomycin (Bruce A. Chabner)60
9 L-Asparaginase (Bruce A. Chabner)64
10 Molecular Targeted Drugs (Jeffrey W. Clark)67
11 Differentiating Agents (Bruce A. Chabner)76
12 Hormonal Agents: Antiestrogens
(Kathrin Strasser-Weippl and Paul E. Goss)81

13 Antiandrogen Therapy (Bruce A. Chabner)88
14 Interferons (Dan L. Longo)91
15 Cytokines, Growth Factors, and Immune-Based Interventions
(Dan L. Longo)96
16 Monoclonal Antibodies in Cancer Treatment (Dan L. Longo) 111
v
SECTION 1
CLASSES OF DRUGS
SECTION 2
HORMONAL AGENTS
SECTION 3
BIOLOGIC RESPONSE MODIFIERS
CONTENTS
17 Bisphosphonates (Matthew R. Smith) 123
18 Febrile Neutropenia (Mark C. Poznansky and Fabrizio Vianello) 127
19 Anemia (James E. Bradner) 136
20 Cancer and Coaguloapthy (Rachel P.G. Rosovsky) 143
21 Metabolic Emergencies in Oncology
(Elizabeth Trice and Ephraim Paul Hochberg) 157
22 Pain Management (Juliet Jacobsen and Vicki Jackson) 178
23 Comprehensive End-of-Life Care (Jennifer Temel) 185
24 Depression, Anxiety, and Fatigue (William F. Pirl) 190
25 Respiratory Emergencies (Tracey Evans) 197
26 Myeloid Malignancies (Karen Ballen) 205
27 Hodgkin’s Disease (Dan L. Longo) 213
28 Non-Hodgkin’s Lymphoma (Yi-Bin Chen, Ephraim Paul Hochberg) 225
29 Acute Lymphoblastic Leukemia and Lymphoma
(Eyal C. Attar and Janet E. Murphy) 247
30 Chronic Lymphocytic Leukemia (Philip C. Amrein) 263
31 Plasma Cell Disorders (Noopur Raje and Dan L. Longo) 275

32 Myelodysplastic Syndromes (Eyal C. Attar) 289
33 Polycythemia Vera (Jerry L. Spivak) 305
34 Idiopathic Myelofibrosis (Jerry L. Spivak) 313
35 Essential Thrombocytosis (Jerry L. Spivak) 322
36 High-Dose Chemotherapy (Yi-Bin Chen) 329
37 Bone Marrow Transplantation (Thomas R. Spitzer) 337
SECTION 5
MYELOID MALIGNANCIES
SECTION 6
LYMPHOID MALIGNANCIES
SECTION 7
MYELODYSPLASTIC SYNDROMES
SECTION 8
MYELOPROLIFERATIVE SYNDROMES
SECTION 9
HIGH-DOSE THERAPY AND
BONE MARROW TRANSPLANT
vi CONTENTS
SECTION 4
SUPPORTIVE CARE
38 Renal Cell Carcinoma
(Abraham B Schwarzberg and M. Dror Michaelson) 345
39 Localized Prostate Cancers (John J. Coen and Douglas M. Dahl) 357
40 Testicular Cancer (Timothy Gilligan) 365
41 Bladder Cancer (Donald S. Kaufman) 373
42 Advanced Prostate Cancer (Matthew R. Smith) 381
43 Esophageal Cancer (Geoffrey Liu) 387
44 Gastric Cancer (Lawrence S. Blaszkowsky) 395
45 Pancreatic Cancer (Jeffrey W. Clark) 402
46 Hepatocellular Carcinoma (Andrew X. Zhu) 410

47 Cholangiocarcinoma and Gallbladder Cancers (Andrew X. Zhu) 416
48 Colon Cancer (David P. Ryan) 423
49 Rectal Cancer (Brian M. Alexander and Theodore S. Hong) 430
50 Anal Cancer (Johanna Bendell) 437
51 Malignant Mesothelioma (Pasi A. Jänne) 445
52 Non-Small Cell Lung Cancer (Lecia V. Sequist) 455
53 Review of Clinical Trials in Thymoma (Panos Fidias) 468
54 Small Cell Lung Cancer (Rebecca Suk Heist) 479
55 Ovarian Cancer (Richard T. Penson) 485
56 Primary Squamous Carcinoma of the Uterine Cervix:
Diagnosis and Management (Marcela G. del Carmen) 497
57 Uterine Cancer (Carolyn Krasner) 503
58 Breast Oncology: Clinical Presentation and Genetics
(Tessa Cigler and Paula D. Ryan) 511
59 Localized Breast Cancer (Beverly Moy) 520
60 Metastatic Breast Cancer (Steven J. Isakoff and Paula D. Ryan) 527
SECTION 10
GU ONCOLOGY
SECTION 11
GI ONCOLOGY
SECTION 12
THORACIC ONCOLOGY
SECTION 13
GYN ONCOLOGY
SECTION 14
BREAST ONCOLOGY
CONTENTS vii
61 Melanoma (Donald P. Lawrence and Krista M. Rubin) 537
62 Soft Tissue and Bone Sarcomas
(Sam S. Yoon, Francis J. Hornicek,

David C. Harmon, and Thomas F. DeLaney) 549
63 Primary Brain Tumors (Andrew S. Chi and Tracy T. Batchelor) 567
64 Metastatic Brain Tumors (April F. Eichler and Scott R. Plotkin) 576
65 Paraneoplastic Neurologic Syndromes
(Kathryn J. Ruddy and Fred H. Hochberg) 583
66 Head and Neck Cancer
(John R. Clark, Paul M. Busse, and Daniel Deschler) 593
Index 611
SECTION 17
NEURO-ONCOLOGY
SECTION 18
HEAD AND NECK CANCER
SECTION 15
MELANOMA
SECTION 16
SARCOMA
viii CONTENTS
CHAPTER 1 Antimetabolites 9
Brian M. Alexander, MD
Resident, Harvard Radiation Oncology Program,
Harvard Medical School;
Department of Radiation Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Philip C. Amrein, MD
Assistant Professor of Medicine,
Harvard Medical School;
Physician,
Massachusetts General Hospital,
Boston, Massachusetts

Eyal C. Attar, MD
Instructor in Medicine,
Harvard Medical School;
Assistant Physician, Center for Leukemia,
Massachusetts General Hospital,
Boston, Massachusetts
Karen Ballen, MD
Associate Professor,
Harvard Medical School;
Director, Center for Leukemia,
Massachusetts General Hospital,
Boston, Massachusetts
Tracy T. Batchelor, MD
Associate Professor of Neurology,
Harvard Medical School;
Executive Director,
Pappas Center for Neuro-Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Johanna Bendell, MD
Assistant Professor,
Division of Oncology and Transplantation,
Department of Medicine,
Duke University Medical Center,
Durham, North Carolina
Lawrence S. Blaszkowsky, MD
Instructor in Medicine,
Harvard Medical School;
Assistant Physician,
Massachusetts General Hospital,

Boston, Massachusetts
ix
CONTRIBUTORS
James E. Bradner, MD
Instructor in Medicine,
Harvard Medical School;
Division of Hematologic Neoplasia,
Dana-Farber Cancer Institute,
Boston, Massachusetts
Paul M. Busse, MD, PhD
Associate Professor of Radiation Oncology,
Harvard Medical School;
Clinical Director,
Chief, Center for Head & Neck Cancers,
Department of Radiation Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Bruce A. Chabner, MD
Professor of Medicine,
Harvard Medical School;
Clinical Director,
Massachusetts General Hospital Cancer Center,
Boston, Massachusetts
Yi-Bin Chen, MD
Clinical Fellow in Medicine,
Harvard Medical School;
Fellow in Hematology/Oncology,
Dana-Farber/Partners CancerCare,
Boston, Massachusetts
Andrew S. Chi, MD, PhD

Fellow in Neuro-Oncology,
Department of Neurology,
Harvard Medical School;
Dana-Farber/Partners CancerCare,
Boston, Massachusetts
Tessa Cigler
Assistant Professor of Medicine,
Weill Cornell Medical College;
Assistant Attending Physician,
New York-Presbyterian Hospital,
New York
Jeffrey W. Clark, MD
Associate Professor of Medicine,
Harvard Medical School;
Associate Physician,
Division of Hematology/Oncology,
Massachusetts General Hospital Cancer Center,
Boston, Massachusetts
x CONTRIBUTORS
John R. Clark, MD
Instructor in Medicine,
Harvard Medical School;
Physician,
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
John J. Coen, MD
Assistant Professor of Radiation Oncology,
Harvard Medical School;
Massachusetts General Hospital,

Boston, Massachusetts
Douglas M. Dahl, MD
Assistant Professor of Surgery,
Harvard Medical School;
Assistant in Urology,
Massachusetts General Hospital,
Boston, Massachusetts
Thomas F. DeLaney, MD
Associate Professor of Radiation Oncology,
Department of Radiation Oncology,
Harvard Medical School;
Medical Director, Francis H. Burr Proton Therapy Center,
Department of Radiation Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Marcela G. del Carmen, MD
Assistant Professor,
Department of Gynecology/Obstetrics,
Harvard Medical School;
Clinical Director,
Gillette Center for Gynecologic Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Daniel Deschler, MD
Director,
Division of Head and Neck Surgery,
Massachusetts Eye and Ear Infirmary,
Boston, Massachusetts
April F. Eichler, MD
Instructor in Neurology,

Harvard Medical School;
Assistant Neurologist,
Massachusetts General Hospital,
Boston, Massachusetts
CONTRIBUTORS xi
Tracey Evans, MD
Assistant Professor of Medicine,
Abramson Cancer Center;
University of Pennsylvania,
Philadelphia, Pennsylvania
Panos Fidias, MD
Assistant Professor,
Harvard Medical School;
Clinical Director, Center for Thoracic Cancers,
Massachusetts General Hospital,
Boston, Massachusetts
Timothy Gilligan, MD
Cleveland Clinic Lerner College of Medicine,
Case Western Reserve University;
Director, Late Effects Clinic,
Co-Director, Hematology-Oncology Fellowship Program,
Taussig Cancer Center,
Cleveland Clinic,
Cleveland, Ohio
Paul E. Goss, MD, PhD FRCPC, FRCP(UK)
Professor of Medicine,
Harvard Medical School;
Director of Breast Cancer Research,
Massachusetts General Hospital,
Co-Director of the Breast Cancer Disease Program,

Dana Farber/Harvard Cancer Center,
Boston, Massachusetts
David C. Harmon, MD
Assistant Professor,
Harvard Medical School;
Physician, Department of Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Rebecca Suk Heist, MD, MPH
Instructor in Medicine,
Harvard Medical School;
Assistant Physician,
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Ephraim Paul Hochberg, M.D.
Instructor in Medicine,
Department of Medicine,
Harvard Medical School;
Assistant Physician, Center for Lymphoma,
Massachusetts General Hospital,
Boston, Massachusetts
xii CONTRIBUTORS
Fred H. Hochberg, MD
Associate Professor of Neurology,
Harvard Medical School;
Physician,
Department of Neurology,
Massachusetts General Hospital,
Boston, Massachusetts

Theodore S. Hong, MD
Instructor in Radiation Oncology,
Harvard Medical School;
Assistant in Radiation Oncology,
Director, Gastrointestinal Radiation Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Francis J. Hornicek, MD, PhD
Associate Professor,
Orthopaedic Surgery,
Harvard Medical School;
Chief, Orthopaedic Oncology Service,
Co-Director, Center for Sarcoma and Connective Tissue Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Steven J. Isakoff, MD, PhD
Instructor in Medicine,
Harvard Medical School;
Assistant in Medicine,
Gillette Center for Breast Cancer, MGH Cancer Center,
Massachusetts General Hospital Cancer Center,
Boston, Massachusetts
Vicki Jackson, MD, MPH
Instructor in Medicine,
Harvard Medical School;
Associate Director and Fellowship Director,
Palliative Care Service,
Massachusetts General Hospital,
Boston, Massachusetts
Juliet Jacobsen, MD, DPH

Instructor in Medicine,
Harvard Medical School;
Assistant in Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Pasi A. Jänne, MD, PhD
Assistant Professor of Medicine,
Harvard Medical School;
Lowe Center for Thoracic Oncology,
Dana-Farber Cancer Institute;
CONTRIBUTORS xiii
Department of Medicine,
Brigham and Women’s Hospital,
Boston, Massachusetts
Donald S. Kaufman, MD
Clinical Professor of Medicine,
Harvard Medical School;
Director, The Claire and John Bertucci Center for Genitourinary Cancers,
Massachusetts General Hospital,
Boston, Massachusetts
Carolyn Krasner, MD
Instructor in Medicine,
Harvard Medical School;
Assistant in Medicine,
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Donald P. Lawrence, MD
Assistant Professor,
Harvard Medical School;

Assistant in Medicine,
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Geoffrey Liu, MD, FRCPC
Assistant Professor,
University of Toronto and Harvard Medical School;
Alan B. Brown Chair in Molecular Genomics,
Princess Margaret Hospital,
Toronto, Ontario, Canada
Dan L. Longo, MD
Scientific Director,
National Institute on Aging,
National Institutes of Health,
Bethesda and Baltimore,
Maryland
M. Dror Michaelson, MD, PhD
Assistant Professor,
Harvard Medical School;
Assistant in Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Beverly Moy, MD, MPH
Instructor in Medicine,
Assistant Physician,
Massachusetts General Hospital,
Boston, Massachusetts
xiv CONTRIBUTORS
Hamza Mujagic, MD, MSc, DRSC
Visiting Scholar and Professor,

Harvard Medical School;
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Janet E. Murphy, MD
Resident,
Department of Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Richard T Penson MD MRCP,
Assistant Professor,
Harvard Medical School;
Clinical Director, Gillette Center for Gynecologic Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
William F. Pirl, MD
Assistant professor in Psychiatry,
Harvard Medical School;
Attending Psychiatrist,
Department of Psychiatry,
Massachusetts General Hospital,
Boston, Massachusetts
Scott R. Plotkin, MD, PhD
Assistant Professor of Neurology,
Harvard Medical School;
Director, Neurofibromatosis Clinic,
Assistant Neurologist,
Department of Neurology,
Massachusetts General Hospital,
Boston, Massachusetts

Mark C. Poznansky, FRCP(E), PhD
Assistant Professor,
Department of Medicine,
Harvard Medical School;
Department of Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Noopur Raje, MD
Assistant Professor,
Department of Medicine,
Harvard Medical School;
Director, Center for Multiple Myeloma,
Division of Hematology/Oncology,
Massachusetts General Hospital Cancer Center,
Boston, Massachusetts
CONTRIBUTORS xv
Rachel P.G. Rosovsky, MD, MPH
Instructor in Medicine,
Harvard Medical School;
Assistant in Medicine,
Massachusetts General Hospital,
Boston, Massachusetts
Krista M. Rubin, NP
Division of Hematology/Oncology,
Center for Melanoma,
Massachusetts General Hospital,
Boston, Massachusetts
Kathryn J. Ruddy, MD
Clinical Fellow in Medicine,
Harvard Medical School;

Fellow in Hematology/Oncology,
Dan-Farber/Partners CancerCare,
Boston, Massachusetts
David P. Ryan, MD
Assistant Professor of Medicine,
Harvard Medical School;
Clinical Director,
Tucker Gosnell Center for Gastrointestinal Cancers,
Massachusetts General Hospital,
Boston, Massachusetts
Paula D. Ryan, MD, PhD
Assistant Professor of Medicine,
Harvard Medical School;
Medical Director,
Breast and Ovarian Cancer Genetics and Risk Assessment Program,
Massachusetts General Hospital,
Boston, Massachusetts
Abraham B Schwarzberg
Clinical Fellow in Medicine,
Harvard Medical School;
Fellow in Hematology/Oncology,
Dan-Farber/Partners CancerCare,
Boston, Massachusetts
Lecia V. Sequist, MD, MPH
Instructor in Medicine,
Harvard Medical School;
Assistant Physician in Medicine,
Department of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts

Matthew R. Smith, M.D., PhD
Associate Professor of Medicine,
Harvard Medical School;
xvi CONTRIBUTORS
Director of Genitourinary Malignancies,
The Claire and John Bertucci Center for Genitourinary Cancers,
Massachusetts General Hospital,
Boston, Massachusetts
Thomas R. Spitzer, MD
Professor of Medicine,
Harvard Medical School;
Director, Bone Marrow Transplant Program,
Massachusetts General Hospital,
Boston, Massachusetts
Jerry L. Spivak, MD
Professor of Medicine and Oncology,
Department of Medicine,
Johns Hopkins University;
Attending Physician, Johns Hopkins Hospital,
Baltimore, Maryland
Kathrin Strasser-Weippl, MD
Center for Hematology and Medical Oncology,
Wilhelminen Hospital,
Vienna, Austria
Jennifer Temel, MD
Instructor in Medicine,
Harvard Medical School;
Assistant in Medicine,
Massachusetts General Hospital,
Boston, Massachusetts

Elizabeth Trice, MD, PhD
Clinical Fellow in Medicine,
Harvard Medical School;
Fellow in Hematology/Oncology,
Dana-Farber/Partners CancerCare,
Boston, Massachusetts
Fabrizio Vianello, MD
Attending Hematologist,
Padua University School of Medicine;
Second Chair of Medicine,
Padova, Italy
Sam S. Yoon, MD
Assistant Professor of Surgery,
Harvard Medical School;
Assistant Surgeon,
Division of Surgical Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
CONTRIBUTORS xvii
Andrew X. Zhu, MD, PhD
Associate Professor,
Harvard Medical School;
Assistant Physician,
Division of Hematology/Oncology,
Massachusetts General Hospital,
Boston, Massachusetts
Dan Zuckerman, MD
Clinical Fellow in Medicine,
Harvard Medical School;
Fellow in Hematology/Oncology,

Dana-Farber/Partners CancerCare,
Boston, Massachusetts
xviii CONTRIBUTORS
CHAPTER 1 Antimetabolites 19
Our intent in writing this book is to provide a concise, straightforward, and
well-referenced manual about cancer chemotherapy and biotherapy and to place
in context the role of such drugs in the treatment of specific malignant diseases.
Further, we offer a condensed version in PDA form for rapid reference on the
ward and in the clinic. As physicians actively involved in teaching and patient
care, we appreciate the challenge of providing a readily digestible resource for
young physicians confronted with a patient with a challenging disease and
potentially fatal disease. We have conceived and written this text with the help
of our colleagues at the Massachusetts General Hospital and elsewhere, and
have intended that it should be particularly useful for a resident training in inter-
nal medicine, surgery, or radiation therapy, as well as for cancer subspecialty
trainees and practicing clinicians. We have attempted to provide relatively com-
plete information on both diseases and drugs, and on the important underlying
rationale for the use of specific therapies in subsets of patients. As a compan-
ion to Harrison’s Textbook of Internal Medicine, this manual is intended to pro-
vide expanded and more detailed coverage of the management of malignant
tumors, with a particular emphasis on their treatment with chemotherapy, target-
ed drugs, and hormonal therapy.
Because of the rapid advance of research in cancer biology and treatment, it
is impossible for a book to keep pace with all current developments; thus a text
such as this must be complemented by the most recent literature and even meet-
ing reports, which are usually available on the internet. We also intend to revise
and update the book and its PDA instrument at regular intervals. Please let us
know of your reaction to the book and its PDA, and offer any suggestions for
their improvement by sending an e-mail to Our hope
is that the manual and PDA will expedite and improve our ability to care for

patients with cancer.
Bruce A. Chabner, M.D.
Thomas J. Lynch, Jr., M.D.
Dan L. Longo, A.B., M.D., F.A.C.P.
PREFACE
xix
ACKNOWLEDGMENTS
This project would have been impossible without the cooperation of multiple
collaborators, who produced their chapters on time and on target, for which we
owe our great appreciation. Once again, our families have given us a pass to
spend evenings and weekends on yet another project, this one being close to our
hearts. Our staff members, particularly Renee Johnson, did an outstanding job
of compiling, editing, and tracking manuscripts, keeping us on course, and reas-
suring our publisher that we would make it to the finish line. In addition, we are
grateful to Pat Duffey and Phil Carrieri for providing essential technical assis-
tance. But most of all, we thank our students, residents and fellows, who con-
stantly challenge us to teach what is important and true, and test our ability to
teach it in an effective and exciting way. If there is joy in oncology, it comes
from two sources; helping our patients, and passing the torch of new knowledge
to the next generation.
xx
INTRODUCTION TO CANCER PHARMACOLOGY
Bruce A. Chabner
The treatment of cancer is a complex undertaking that involves, in most
patients, a co-ordination of efforts from multiple specialties. Virtually all
patients require surgery to establish the diagnosis and to remove the primary
tumor, but this effort is only the first part of an extended plan that, with increas-
ing frequency, includes chemotherapy or biological therapy and irradiation. In
the succeeding chapters we present the basic information needed by an oncolo-
gist for understanding the use of drugs. This information is essential for

informed decision making by the medical oncologist or pediatric oncologist, but
enhances the integration of treatment planning by the other specialists, who
need to know what to expect of their medical colleagues.
In these chapters we present essential information on the mechanism of
action, and determinants of response for the standard drugs. In addition, and of
particular interest for the medical oncologist, we include valuable data on phar-
macokinetics, clearance mechanisms, drug interactions, dose modification for
organ dysfunction, and pharmacogenetics, all of which may influence the
response to treatment and the development of toxicity. For those that require
more detailed information or references, we suggest that the reader consult
more comprehensive and specialized texts (1–3).
While individualization of treatment is necessary in certain therapeutic set-
tings, in general readers are urged to administer drugs according to standard and
well-tested protocols, and to recognize that intervention with new drugs, with
irradiation, or with biological agents in previously unexplored ways may lead to
unanticipated toxicity. New interventions or treatment regimens that carry
potential risk and uncertain benefit must first be tested in clinical trials to prove
their safety and efficacy, with appropriate oversight and approval by an
Investigational Review Board.
Finally, it is important for the clinical oncologist to remember that all drugs
pose risks and that their use constitutes a balance of risk and benefit. We provide
here the latest information available as we go to press. However, because cancer is
a potentially fatal disease, drugs are approved after relatively limited clinical test-
ing, and carry incompletely defined potential for toxicity at the time of their first
marketing. Cancer drug toxicity affects not only the bone marrow, but extends
across a broad spectrum that includes coagulopathy, changes in mental status,
immune modulation, cardiovascular effects, pulmonary, hepatic, and renal damage,
and second malignancy. With increasing use, these side effects, as well as new indi-
cations for the agent, are appreciated and become the subject of FDA alerts pub-
lished in major cancer journals. It is encumbent upon the oncologist to keep abreast

of this new information for both the benefit and the safety of our patients.
REFERENCES
1. Chabner BA, Amrein PC, Druker BJ, et al. Antineoplastic Agents. In JG
Hardman and LE Limbird(eds.) “Goodman and Gilmans the Pharmacological
Basis of Therapeutics”, 11th edition. McGraw-Hill, New York, NY: 2005.
2. Chabner BA. In BA Chabner and DL Longo(eds.), “Cancer Chemotherapy and
Biotherapy Principles and Practice”, 4th edition, Lippincott Williams &
Wilkins Philadelphia, PA, 2006.
3. Kufe DW, Bast Jr, RC, Hait WN, Hong WK, Pollock RE, Weichselbaum RR,
Holland JF, Frei III E(eds.), Cancer Medicine, 7th edition. BC Decker Inc,
Hamiltion, Unt., 2006.
xxi
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1
1
ANTIMETABOLITES: FLUOROPYRIMIDINES
AND OTHER AGENTS
Bruce A. Chabner
1
FLUOROPYRIMIDINES
5-fluoro-uracil (5-FU) and its prodrug, capecitabine (4-pentoxycarbonyl-5′-
deoxy-5-fluorocytidine), are central agents in the treatment of epithelial can-
cers, particularly cancers of the breast, head and neck, and gastrointestinal tract.
They have synergistic interaction with other cytotoxic agents, such as cisplatin
or oxaliplatin, with antiangiogenic drugs, and with radiation therapy. As a com-
ponent of adjuvant and metastatic therapy, fluoropyrimidines have improved
survival in patients with colorectal cancer (1).
Mechanism of Action and Resistance
The first agent of this class, 5-FU (Figure 1-1), was synthesized in 1956 by
Heidelberger, based on experiments that demonstrated the ability of tumor cells

to salvage uracil for DNA synthesis. Later work showed that 5-FU is converted
to an active deoxynucleotide, FdUMP, a potent inhibitor of DNA synthesis. Its
activation occurs by one of several pathways, as shown in Figure 1-1.
SECTION 1
CLASSES OF DRUGS
FIGURE 1-1 Routes of activation (via TP and TK) and inactivation (via DPD) of
5-fluorouracil (5-FU).
N
5,
N
10
-Methylene-telrahydrofolate
H
2
N
N
N
N
Glu
N
N
H
H
H
H
CH
2
H
2
C

OH
O
N
H
H
H
HH
H
HS
O
O
HO
F
HN
P
H
2
N
N
N
N
H
Glu
N
N
H
H
H
H
CH

2
H
2
C
OH
O
H
H
S
H
H
HH
H
O
O
HO
F
HN
P
Ternary
Complex
Thymidylate
synthase
Thymidylate
synthase
Thymidine Kinase
(TK)
Thymidine
Phosphorylase
(TP)

Dihydropyrimidine
Dehydrogenase
(DPD)
N
H
F
O
O
HN
5-Fu
Dihydro 5-FU
FdUMP
N
H
H
F
O
H
O
HN